The overall objective of this proposal is to develop a means to identify people who display genomic sensitivity to ionizing radiation and to determine the basis of chromatin sensitivity in such individuals to DNA damaging agents. Recent studies have yielded important information about the relationship between genomic instability and cancer proneness. Direct evidence for a correlation between the genomic instability and cancer proneness comes from inherited recessive syndromes such as ataxia telangiectasia (AT). Cells derived from AT individials exhibit increased genomic sensitivity to ionizing radiation. The underlying basis for such sensitivity is not well understood. Several studies suggest that intrinsic chromatin structure, particularly at the neds of chromosomes, might play a role in the genomic sensitivity in AT. Because a chromatin defect in AT appears at chromosome ends, the focus of this proposal is on questions related to whether chromosome end associations are permanent structures; whether they are resolved through the cell cycle; and whether such associations are due to a defect in DNA and/or in the nuclear matrix. The investigators will address these questions by comparing telomeric fusions, telomeric sequences at chromosome ends, telomere length, telomerase activity, telomere-nuclear matrix associations and the periodicity of nucleosomes in telomere regions, among AT and normal cell lines. Results from these proposed studies are likely to provide important information on the mechanism of the predisposition of AT cells to genomic instability and chromosome aberrations.